Process for making montelukast and intermediates therefor

ABSTRACT

A process for making montelukast, a pharmaceutically useful compound of the following formula and salts thereof: 
     
       
         
         
             
             
         
       
     
     using a compound of formula (11) 
     
       
         
         
             
             
         
       
     
     is provided.

This application is a Divisional of U.S. patent application Ser. No.11/561,689, filed Nov. 20, 2006, the entire contents of which areincorporated herein by reference, which application claims the benefitof priority under 35 U.S.C. § 119(e) from U.S. provisional patentapplication Ser. No. 60/737,752, filed Nov. 18, 2005; Ser. No.60/794,429, filed Apr. 24, 2006; and Ser. No. 60/824,382, filed Sep. 1,2006, the entire contents of each provisional application beingincorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to the synthesis of montelukast, apharmaceutical agent, as well as to intermediates and processes usefulin the synthesis.

Montelukast, chemically[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, has the following structure of formula (1):

Montelukast monosodium salt (montelukast sodium) is commonly used fortreatment of asthma and/or seasonal allergies. It is marketed under thebrand name SINGULAIR® (Merck) in the form of oral tablets, chewabletablets, and granules.

U.S. Pat. No. 5,565,473 to Belley et al. (see also corresponding EP 0480 717) discloses a genus of pharmaceutically useful compounds thatencompasses montelukast and salts thereof. Example 161 in connectionwith example 146 of U.S. Pat. No. 5,565,473 disclose the synthesis ofmontelukast sodium as follows:

THP as used herein means tetrahydropyranyl group.

Many other synthetic schemes are proposed in U.S. Pat. No. 5,565,473 formaking unsaturated hydroxyalkylquinoline acids, which may genericallyinclude montelukast. However, none of these other schemes werespecifically applied to making montelukast. For example, Method B inU.S. Pat. No. 5,565,473 comprises reacting a compound of “generalformula (XII)” with an organometallic compound of formula R²M to give acompound of “general formula (Ia)”. Applying the correspondingsubstituent groups for montelukast, the method would follow the schemebelow, wherein the compound of formula (2) is the representativecompound of “general formula (XII)”:

M is suggested to be MgBr or Li in Method A. The only disclosed processfor making the compounds of “general formula (XII)” is not desirable formaking montelukast, i.e. for making the hypothetical compound of formula(2). Specifically the process in Method B calls for a coupling reactionwith a compound of “general formula (XI).” If applied to thecorresponding substituents for montelukast, the reaction would be asfollows:

But this process cannot provide the compound (2) stereoselectively inthe R-configuration as suggested above, which is required for themontelukast synthesis. Instead, only a racemic product may be obtainedand no method has been suggested how to resolve the racemate into singleenantiomers.

A suitable process for making montelukast starts from a methyl estercompound (18).

The compound (18) is a known compound of the prior art (see CompoundXXVII in EP 480717) and can be produced by Steps 1-2 of the example 146in EP 480717. It can be isolated in solid form as a monohydrate.

In an earlier patent application by some of the present inventors,Published Application No. US-2005-0245568-A1 filed Mar. 17, 2005, anacetylthio ester compound of formula (20)

was disclosed as an intermediate in a process for making montelukast andmay be produced from the compound (18) as shown in the followingreaction scheme:

The compound (20) may be reacted, optionally after its conversion to thethiol compound (3)

by treatment with hydrazine as described more fully in theabove-mentioned US-2005-0245568, with a compound of formula (5):

wherein in the above formulas R is hydrogen or C1-C4 alkyl group, and Lis a leaving group selected from a halogen or an alkyl- oraryl-sulfonyloxy group, to form a compound of formula (2) as in U.S.Pat. No. 5,565,473, or more generally (2a):

wherein R is H or a C1-C4 alkyl group. Thus, when R is hydrogen informula (5), the compound (2) is directly formed. When R is a C1-C4alkyl group in formula (5), then the compound of formula (2a) is formed.L is described as typically representing a chloro, bromo, mesyloxy,besyloxy or tosyloxy group. The reaction can take place in an inertsolvent in the presence of a base and preferably under the atmosphere ofan inert gas. The compounds of formula (2) and (2a) can be converted tomontelukast or a salt thereof, generally by methylmagnesium halide, asshown in U.S. Pat. No. 5,565,473, optionally with hydrolysis.

In an alternate reaction pathway, which has been disclosed in anotherapplication filed by some of the present inventors—Published ApplicationUS-2005-0245569-A1 filed Mar. 17, 2005—the compound (20) is subjected toa reaction with methyl lithium in an inert solvent such astetrahydrofuran, to form compound (6) as shown in the following reactionscheme:

In a next step, the compound (4) is made in situ from the compound offormula (6) by a reaction with hydrazine and it may be subsequentlyconverted to montelukast. The reaction scheme can be expressed asfollows:

It would be desirable to provide an alternate way to make montelukastwhich would be suitable for a large scale production and/or to improvethe above described various methods. In particular, processes that canachieve good yields and high purity and that can be reliably controlledare important in industrial pharmaceutical chemistry.

SUMMARY OF THE INVENTION

The present invention relates to the discovery of intermediates andprocesses associated with the synthesis of montelukast.

A first aspect of the invention relates to a thiolactone compound offormula (11) (which is(3R)-{3-[(E)-2(7-chloro-2-quinolinyl)vinyl]phenyl}-4,5-dihydro-3H-benzo[c]thiepin-1-one)and salts thereof:

The compound can be obtained in solid state, e.g., as a crystallinematerial, as the free base or as a salt. A useful salt is thehydrochloride, especially in the context of carrying out purification ofthe compound.

A second aspect of the invention relates to a process of making thecompound of formula (11) comprising the following sequence:

The process can include the isolation and, if desired, purification ofthe compound (11) optionally as a salt.

A third aspect of the invention relates to a process of using thecompound of formula (11), which comprises reacting a compound of formula(11)

or an acid addition salt thereof with a methylmagnesium halide selectedfrom methylmagnesium chloride, methylmagnesium bromide, methylmagnesiumiodide, and combinations thereof, to form a compound of formula (4)

The compound (11) can be used in an isolated and/or purified form. Thecompound of formula (4) can then be converted to montelukast and relatedcompounds by various ways, especially by the following sequence:

The conversion from (1a) to (1) assumes that R is not hydrogen and is,obviously unnecessary when R is hydrogen. The overall process has theadvantage in providing suitable intermediate(s) that may be isolated insolid state and purified, and does not require the use of toxichydrazine for the production process of making compound (4) from thecompound (20).

A fourth aspect of the invention relates to a process for purifyingmontelukast acid which comprises at least one of the following steps:

i) filtering a toluene solution of montelukast acid through a polarsorbent, such as silica gel, and optionally precipitating themontelukast acid; andii) crystallizing montelukast acid from a protic solvent such as ethanolin the absence of light.

The two steps can be used in combination and/or an individual step canbe repeated one or more times.

DETAILED DESCRIPTION OF THE INVENTION

References to compounds or formulas throughout the specification includethe base as well as the acid addition salts thereof, unless otherwisespecified. Also, the word “isolated” as used throughout refers toseparating the target compound from at least a portion of itsenvironment so as to recover the target compound in a more concentratedform. Typically the isolation step involves a phase separation techniquewherein the target compound is preferentially obtained in one phasewhereby it is more easily recovered in a more concentrated form.Traditional examples of isolation techniques include precipitationand/or crystallization (e.g., solid-liquid separations), evaporating ordistilling off all or a portion of the solvent(s) (e.g., vapor-liquidseparations), liquid-liquid phase separations such as by extractions ordecanting, etc. While isolation can and frequently does have apurification effect, it is not required that impurities per se arereduced or removed.

The starting material for making the compound (11) of the presentinvention is the compound of formula (20), which may be obtained by aprocess starting from a methyl ester compound (18) as shown in thefollowing reaction scheme:

The compound (18) is a known compound. It can be isolated in solid formas a monohydrate. As the compound (18) is a well defined solid material,it is a very convenient starting material for the whole montelukastsynthesis.

A suitable process for conversion of the compound (18) into compound(20) comprises the following sequence:

In the first step, the OH— group in (18) is first made labile byconverting it into a reactive group L such as an alkyl- oraryl-sulfonyloxy group, preferably a mesyloxy group. The product is thecompound of general formula (19) and the compound bearing the mesyloxygroup (19a) is typically preferred.

The mesylation reaction comprises contacting compound (18) withmethanesulfonyl chloride in an inert solvent in the presence of asuitable base, e.g. a tertiary amine such as triethylamine.

The labile compound (19) is then converted into an acetylthio estercompound (20) by reaction with a thioacetic acid or salt thereof, forinstance sodium or potassium thioacetate, in an inert solvent. If thethioacetic acid is used, a base, e.g. triethylamine, is typically alsopresent. In this way, the labile L-group is replaced by the CH₃—CO—S—group. The reaction normally proceeds in a suitable inert solvent suchas toluene, dimethylformamide or mixtures thereof, and generally attemperatures close to and including ambient, e.g. 0-60° C.

After conventional work-up of the reaction mixture, the compound (20) istypically isolated as a free base, which is an oil. The presentinventors however found out that the base (20), albeit a very week base,may be converted into acid addition salts, some of which. may beisolated as solid compounds. From this aspect, the preferred salts arethe hydrochloride (20a) and the benzenesulfonate (20 b),

also suitable are the p-toluenesulfonate (20c) and the sulfate (20d).The isolation of compound (20) in a solid form is normally connectedwith a purification effect, as many of the side products remain in thereaction mixture. Also the optical purity of the isolated product isgenerally higher than when the compound (20) would be isolated as a freebase.

The acid addition salts may be prepared by contacting the compound (20)with the corresponding acid in a suitable solvent, such as an C2-C8aliphatic ketone, e.g., acetone, C2-C8 aliphatic ester, e.g., ethylacetate, C1-C4 aliphatic alcohol, e.g. isopropanol, a C2-C15 aliphaticamide such as dimethylformamide, and mixtures thereof. The temperatureof the contact may be from −20° C. to the boiling point of the solvent.The salt generally precipitates spontaneously and may be isolated atambient temperature or at a temperature close to ambient, typically at0-35° C. After isolation of the compound (20) as an acid addition salt,and preferably as the hydrochloride (20a), the product can have chemicalpurity of 99% or and optical purity of 98% or higher.

The isolated salt of the compound (20) may be converted back to the freebase or used as the salt in the next reaction step. The overalladvantage of these steps is that the compound (20) is isolated in asolid, stable and well processible form and the isolation of the saltbrings the possibility of purification of the compound (20) before thenext reaction steps. The hydrochloride (20a) and the besylate (20b) thusform a particular aspect of the present invention.

The compound (20) can then be converted into the intermediate compound(11). The conversion is generally performed by reacting the compound(20) with a methylmagnesium halide, preferably methylmagnesium chloride,bromide, or iodide. Typically the reaction is carried out in an inertsolvent such as toluene with 2-3 molar equivalents of an etheralsolution of methylmagnesium halide. The temperature of reactiongenerally should not exceed 10° C. and is preferably between 0° and 5°C., though higher temperatures can be used especially later in thereaction. The reaction time is preferably from 1 to 6 hours. The courseof reaction may be monitored by a suitable analytical technique, e.g. byHPLC. After the reaction is completed, the reaction mixture is worked upby treatment with water (preferably acidified water such as a dilutedacetic acid), the product is preferably extracted by an organic solventand isolated from the solvent.

The crude solid product (11), as obtained, may be further purified byany suitable technique such as through crystallization or by columnchromatography, to obtain the desired degree of purity, if needed.Advantageously, the compound (11) may be purified by crystallizationfrom a solvent comprising a mixture of a cyclic ether liquid (e.g.tetrahydrofuran or dioxan) and a second liquid selected from a C1-C4alcohol (e.g. methanol or ethanol), C2-C6 ester (e.g. ethyl acetate),C4-C8 hydrocarbon (e.g. toluene), C3-C8 ketone (e.g. acetone) andmixtures thereof. The crystallization may be performed (i) by dissolvingthe compound (11) in a hot solvent mixture followed by cooling thesolution, (ii) by adding the second liquid as an antisolvent to asolution of compound (11) in the cyclic ether liquid, or (iii) by acombination of these cooling and antisolvent techniques. Alternativelypurification can be achieved by crystallizing the compound (11) as anacid addition salt. Generally the compound (11) is treated or combinedwith an organic or inorganic acid to form a salt. For example contactingwith hydrochloric acid forms the hydrochloride (11a).

The salt, and preferably the hydrochloride salt (11a), may be isolatedin solid state from the reaction mixture, whereby most of the sideproducts and residual reagents remain in the mother liquor. This saltmay be converted back to the free base by treatment with a suitableorganic or inorganic base, whereby the compound (11) is obtained in ahigher degree of purity, though it is not required in order to carry outthe next reaction steps.

Advantageously, the compound (11) has a chemical and/or optical-purityof at least 90% and may even exhibit 98% purity or higher.

The hydrochloride salt of the formula (11a) forms a particular aspect ofthe invention. The product (11), especially its salt such as (11a), maybe stored at conventional storage conditions without a loss of quality,which is advantageous particularly at industrial scale.

In the next steps the compound (11) is converted to montelukast. In atypical scheme, the process goes via the intermediate of the formula (4)or a salt thereof

The compound (11) is treated with a methylmagnesium halide, i.e.methylmagnesium chloride, bromide or iodide, in an etheral solvent, suchas in tetrahydrofuran, optionally under the presence of an inertco-solvent such as toluene, to make the compound (4). At least two molarequivalents of the methylmagnesium reagent are necessary, butadvantageously 3-8 equivalents may be used. The reaction temperature isgenerally within the range of −15° to 15° C.

It has been found out that a serious amount of an impurity appears inthis reaction step. This impurity is a ketone of the formula (12),

which is a natural intermediate and the primary product of thering-opening reaction on the compound (11). One may expect that thisketone will react with the next equivalent of methylmagnesium halide toform the desired tertiary alcohol (4), but this happens only to acertain extent and 10-20% of the ketone typically remains in thereaction mixture even under a presence of large molar excess of themethylmagnesium halide and prolonged treatment. It is theorized thatthis is because the compound (12) is prone to enolization, whichprevents the compound from further reactions. However, it has beendiscovered that the formation of the compound (12) in the reactionmixture may be minimized by adding a cerium (III) salt, for instancecerium trichloride, to the reaction mixture, which suppresses theenolization and therefore affords more complete conversion of thecompound (12). The cerium (III) salt may advantageously be an activatedcerium (III) salt. The activity of a cerium (III) salt can be enhancedby conditioning or incubating the salt with an ethereal solvent such asa cyclic ether, e.g. tetrahydrofuran, before its use. A cerium (III)salt that exhibits enhanced activity as a result of such conditioning isan “activated cerium (III) salt.” Conveniently the cerium (III) salt isadded in a solution or suspension of a cyclic ether, preferablytetrahydrofuran, whereby the salt and cyclic ether have been in a mutualcontact for at least 4 hours, typically at least 8 hours, and in someembodiments at least 12 hours, prior to the use of the reagent. In sucha way, the activity of the cerium (III) salt is substantially enhanced;allowing the use of an “activated cerium (III) salt.” In the case ofmethylmagnesium chloride or bromide, it was observed that the presenceof the activated cerium (III) salt is especially important as these twohalides would otherwise provide very low conversion rates. The amount ofthe cerium compound is at least one molar equivalent, and advantageously2-4 molar equivalents. By using the cerium (III) salt, and preferablythe activated cerium (III) salt, the amount of the ketone compound (12)remaining in the reaction mixture may be less than 5% and even less than1%. The course of the reaction may be monitored by a suitable analyticalmethod, e.g. by HPLC.

After a conventional workup (a decomposition of the magnesium-comprisingcomplex by an acidified water), a solution of the compound (4) in theinert solvent may be used immediately for the next reaction step or theinert solvent can be evaporated first. Generally, however, the compound(4) is isolated as a salt as described in more detail below.

In an alternative process, the compound (4) may also be made directlyfrom the compound (20) without the isolation of the compound (11) byusing considerable excess of the methylmagnesium halide, particularlymethylmagnesium iodide. This process has been suggested in the CN1420113A. In this process, the same problem of the ketone impurity (12)arises as it is also formed in considerable amounts (5-10%). It has beendiscovered that a cerium (III) salt, for instance cerium trichloride,and preferably the above defined activated cerium (III) salt, may beused for the activation of methylmagnesium halide. This way, the amountof the ketone impurity is surprisingly minimized and the process isconsiderably improved. In addition, methylmagnesium chloride or bromidemay be used for the reaction upon such modification as it has beenobserved that only the methylmagnesium iodide reacts under theconditions disclosed in the CN 1420113.

The compound (4), when prepared by any of the synthetic processesdescribed above, is not generally isolable in a solid state as the base.Therefore, the purification of it, whenever desired, is problematic.However, the compound (4) may be converted into an acid addition salt,that is crystalline. By precipitating out the crystalline salt from thereaction mixture, the overall purity of the compound (4) is improved asmany of the side products, and particularly the ketone impurity, remainin the solution.

Suitable salts of the compound (4) that may be precipitated in a solidstate are the hydrochloride (4a), the tosylate (4b) and the besylate(4c).

In an advantageous mode, the salts of the compound (4) and particularlythe compounds (4a), (4b) or (4c) may be prepared in the solid state byreacting the solution of the compound (4), e.g. in toluene, with theequivalent amount of the corresponding acid at ambient temperature. Anantisolvent that induces or improves the precipitation (e.g. ethylacetate) may be added subsequently for improving the process.

In an example, the original 80% purity of the compound (4) may beenhanced to 96% purity of the precipitated tosylate (4b) or besylate(4c) by this simple process. In particular, the undesired keto-impuritymay be removed from the product this way.

In addition, the salts are a suitable means for storing the compound (4)for an extended time without substantive decomposition (the compound (4)is inherently very unstable compound). From this aspect, the compounds(4b) and (4c) are particularly suitable as they may be isolated as acrystalline stable material. Furthermore, the salts (4a), (4b) and (4c)may serve as analytical standards for monitoring the quality of thecompound (4) and/or the course of a reaction employing the compound (4).

For further steps in the process of making montelukast, the salt may beeasily converted back to the compound (4) by neutralization with asuitable base, or it can be used as the salt. In a next step, thecompound (4) (as a base and/or as a salt thereof) is subjected to areaction with a compound of formula (5).

The R in the compound of formula (5) may be hydrogen or a C1-C4 alkylgroup, and preferably is a methyl or ethyl group. The leaving group Lmay be halogen or/and alkyl- or arylsulfonyloxy group.

The thiol intermediate (4), if not converted to a salt, is very prone tospontaneous side reactions, particularly involving the oxidation of thethiol group into a disulfide group. Thus whenever the base (4) is usedafter the cleavage step, the compound of formula (5) should be addedshortly thereafter in order to reduce impurities/side-products;generally within three hours and typically within one hour. Similarly,if (4) is converted to a salt and re-converted back to the base, thereaction with the compound (5) should be relatively immediate after there-conversion. Such timing issues are less important for the salts ofcompound (4), which can even be stored in solid state for later use. Thelatter are more stable to such side reactions while still maintainingsufficient reactivity for the reaction with compound (5). In practice,if the compound (4) is used in its base form, it is dissolved/dispersedin an ethereal solvent such as tetrahydrofuran.

Typically, an alkaline hydroxide or alkoxide, such as lithium hydroxideor sodium methoxide, serves as a base in the nucleophilic substitutionof the side chain of (5). The reaction normally proceeds in a solventwhich is typically a solvent mixture comprising an alcohol, for instancea methanol/acetonitrile mixture or methanol/tetrahydrofuran mixture. Thereaction is generally carried out under an atmosphere of an inert gas,such as nitrogen or argon. The combination of the above conditionsserves to minimize the undesired side reaction of the thiol group into adisulfide group.

In the previously mentioned published patent applications, the preferredcompound of the general formula (5) for making montelukast was thebromo-ester of the formula (5a).

The present inventors found out, however, that this compound undergoes aserious side reaction under the desired reaction conditions,particularly to a re-arrangement yielding a cyclobutane derivative ofring structure (5-1), often followed by the product of the ring openingof the structure (5-2).

Both side products are similarly reactive as the compound (5a) itself,thus yielding a row of impurities structurally related to montelukast,which may be removed from the desired product only with difficulties.

From this aspect, the more preferable reagent for the montelukastsynthesis is the p-methoxybenzene sulfonyloxy compound of formula (5b),

wherein R′ is a C1-C4 straight or branched alkyl group and preferably ismethyl group.

The presence of p-methoxy group in the molecule provides anelectron-donating effect which is sufficiently high to achieve thedesired improved stability and sufficiently low that reactivity with theintended reaction partner is maintained.

The methyl ester [(5b), R=methyl] has chemical stability similar to thecorresponding bromo-compound (5a), but it is more stable than, forinstance, analogous methanesulfonyloxy-, p-toluenesulfonyloxy- orbenzenesulfonyloxy compounds (which are so unstable that they can beisolated only with difficulties). This compound has a lower tendency tothe rearrangement and ring-opening reaction shown above for thebromo-compound. And it is very well detectable in UV-light at theconventional wavelength 254 nm, which is useful for monitoring thereaction process by HPLC with UV detection. Accordingly, the compound(5b) and particularly the methyl ester, forms a specific aspect of thepresent invention.

The compound (5b) may be produced by any process known in the art formaking of compounds of the general formula (5). In particular, it may beproduced by reacting the compound of formula (15)

wherein R is a C1-C4 alkyl group, with p-methoxybenzenesulfonyl halide,particularly p-methoxybenzenesulfonyl-chloride in a presence of a base,preferably pyridine, according to the scheme:

It is useful in any process for making montelukast, i.e. not only forthe reaction with the compound of formula (4) as preferred within thepresent invention, but, e.g., also in a process using the compound offormula (20) or (3) as the reaction partner.

When the product of the reaction with compound (5) is an ester compoundof formula (1a),

wherein R is C1-C4 alkyl group, and typically is methyl group, it isnormally converted by hydrolysis to provide the desired montelukastcompound (1). Preferred hydrolytic conditions comprise an alkalinehydrolysis. Advantageously, the hydrolysis occurs directly in thereaction mixture after the coupling of the compound (4) with thecompound (5). To achieve this, the reaction mixture comprises at leastan equimolar amount of water (which may be added or may be inherentlypresent).

The final product of the process is montelukast acid. It may be used inpharmaceutical applications per se, for instance in a solid form, whichhas been disclosed in U.S. Patent Publication US-2005-0107426-A1 filedOct. 8, 2004, entitled “Solid State Montolukast,” the entire contents ofwhich are incorporated herein by reference. Alternatively, themontelukast acid may be converted into various salts, of which thesodium salt is preferred, by known methods.

Several important observations should be included:

a) The role of cerium (III) compounds is substantive also in otherprocesses for making montelukast, in which methylmagnesium halide isused for reductive methylation on an ester group. For instance, theconversion of the compound (2) to montelukast of formula (1) disclosedin the earlier published patent application US-2005-0245568-A1 andoutlined above may suffer from the same problem of the formation of astable keto-intermediate, which have the formula (13) and (14)respectively,

and which may form an impurity in the desired product. The addition ofcerium trichloride, and preferably the activated cerium trichloride tothe methylmagnesium halide is a measure that substantively minimizes theamounts of this impurity in montelukast.

b) The importance of minimizing the side products, and particularly thecompound (12) in the reaction process in making montelukast according tothis invention, becomes apparent from the finding that the side productof formula (12) undergoes basically the same reaction pathway as themain reagent. Thus, whenever present as an impurity in the compound (4),it also reacts with the compound (5), and the impurity of the formula(13), typically the methyl ester of the formula (13a),

is formed. Upon saponification under conventional conditions leading tomontelukast acid, it is also saponified to form an impurity of formula(14), which is very difficult to be removed from the final montelukast.

In conclusion, it should be also noted that, in essence, any productionprocess for making montelukast, which uses a methylmagnesium halide as areagent with an ester group, may face the problem of formation of acorresponding keto-impurity analogous to the compound of formula (12)above, and particularly the problem of formation of the compounds (13)and (14). Accordingly, such reaction process must be monitored for thepresence of the compounds (12), (13) and/or (14) and appropriatemeasures must be made to suppress their formation. One of such measuresis the addition of cerium (III) salts to methylmagnesium halide asexemplified above, but it is not excluded that also other ways may befound including purification processes. In consequence, the compounds(12), (13) and (14) are useful chemical products per se, as they mayserve as reference standards in the step of monitoring the process ofmaking montelukast, particularly when starting from the compound (20).Thus, a process of making montelukast from the compound (20) may beadvantageously improved in such a way, that the relevant production step(e.g. a step using the compound (20), (11), (2) or (2a) as a substratefor the reaction with methylmagnesium halide) is monitored for thepresence of the appropriate member of the group of the compounds(12),(13) and (14) and no subsequent reaction step is started unless thecontent of this relevant compound is below the stated limit, which couldbe less than 5% but preferably less than 1%. Therefore, the abovedescribed processes, with or without monitoring are capable ofproviding, and preferably do provide, a montelukast having the contentof any of the impurities (12), (13) and/or (14) lower than 1%, and/orhaving a chromatographic purity higher than 99%. Such a high purity isadvantageous in the production of a pharmaceutical.

In as much as several aspects of the present invention can be used inother related syntheses of montelukast, which do not involve thethiolactone compound of formula (11), the following flow chartillustrates the wide applicability of, e.g. the use of cerium salts, theuse of compound (5b), the purification of compound (20), the monitoringof certain kinds of impurities, etc., to various synthesis schemes, allof which are considered part of the invention.

It should be understood that the reagents shown are not compulsory andnot all steps or conditions are illustrated; e.g., the hydrolysis stepof an ester compound to an acid compound may optionally be performedamong other steps not explicitly shown. Further, while all compounds arederived in the scheme from compound (20), in practice, many of theintermediate compounds such as compound (4) and (2) can be made fromother starting materials such as by the methods generally taught inBelley et al.

Once the montelukast is formed, it is often desirable to purify it to,e.g., pharmaceutically acceptable quality. Typically, the montelukastacid is purified before its conversion to the sodium salt. Thepurification at this stage is easier and more effective than it would beif performed with the final montelukast sodium. It is known that themontelukast acid may be converted into a salt with dicyclohexyl amine,or with 1-amino adamantane as shown in U.S. provisional patentapplication Ser. No. 60/783,027, filed Mar. 17, 2006, whereby suchconversions exhibit a purification effect. However, it has beendiscovered that it is possible to purify the crude montelukast acideffectively without a conversion thereof into a salt. The improvedprocess comprises at least one of the following steps:

i) Filtration of the toluene solution of montelukast acid through apolar sorbent, such as silica gel, optionally followed by precipitation;and

ii) Crystallization from a protic solvent such as ethanol under theabsence of light.

The toluene is an advantageous solvent for the crystallization, as, onthe contrary to many other solvents, substantially no trans-cisisomerisation on the double bond occurs. The polar sorbent effectivelyremoves the oxidation products, which are particularly formed when theunstable intermediate (4) is used within the synthetic process. Thealcoholic solvent effectively removes side products from thecondensation of the compound (4) and (5), particularly products formedby rearrangement of the cyclopropane ring. The absence of lightminimizes the trans-cis isomerisation.

Advantageously, both of the steps are performed in the purificationprocess. The steps, when using more than one, can be employed in anyorder and any step may be repeated one or more times. By this, themontelukast of a purity of more than 99%, and even more than 99.5%, canbe obtained.

The montelukast can be converted into montelukast salt, such as thesodium salt, by known techniques. A useful solid state form for the saltmontelukast sodium is the amorphous form. It can be made by contactingmontelukast sodium with an aliphatic C₅-C₁₀ straight or branchedhydrocarbon solvent such as petroleum ether, hexane, heptane andmixtures thereof, and precipitating amorphous montelukast sodium. Then-heptane is generally the preferred solvent. Normally the solvent isstirred during, (at least), the contacting with the montelukast sodium.In an advantageous mode, montelukast acid is converted into themontelukast sodium by contacting thereof with sodium hydroxide oralkoxide in an organic water miscible solvent, followed by removal ofthe solvent, and the concentrate (which is typically a liquid or an oil)is slowly added into the stirred hydrocarbon liquid, whereby theamorphous montelukast sodium precipitates. The temperature of theprecipitation is advantageously ambient temperature.

The invention is further described by way of the following non-limitingexamples.

Throughout the whole description and unless stated to the contrary, thedouble bond attached to the 7-chloro-2-quinolinyl ring has, in all theformulas, the two non-hydrogen substituents in the same configuration asthat in montelukast.

EXAMPLE 1 Compound (11)

Step 1—Compound (20)

500 g of Methyl2-((3S)-3-[2-(7-chloro-2-quinolinyl)-ethenyl]-phenyl)-3-hydroxypropyl)-benzoatemonohydrate [Compound (18)] were placed into reactor and 3000 ml oftoluene were added. The mixture of toluene/water was azeotropicallydistilled off (800 ml). Then the toluene solution was cooled to roomtemperature. The solution contained 480.11 g of anhydrous (18).

To the solution, 227.0 ml of triethylamine were added at roomtemperature and 110.2 ml of methanesulfonyl chloride were added dropwiseso that reaction temperature did not exceed 40° C. Reaction mixture wassubsequently stirred at 25-30° C. for 1 hour. Then 605 ml oftriethylamine were added to the reaction mixture followed by addition of156 ml of thioacetic acid at room temperature within 5 minutes. Thereaction mixture was subsequently heated to 40-45° C. for 3.5 hours.1000 ml of water were added to the reaction mixture and it was stirredfor 15 minutes. The layers were separated, organic layer wassubsequently washed with 2×1000 ml of brine and most of toluene wasdistilled off by vacuum distillation. The resulting solution wasfiltered and the residual toluene evaporated to dryness on the rotaryevaporator giving orange-brown oily residue of crude compound (20).

Yield: 588 g (104.3%)

Step 2—Compound (11)

Work under argon.

24.40 g of the compound (20) (crude from Example 1) were dissolved in260 ml of anhydrous toluene (distilled from benzophenone/Na). Solutionwas cooled to 0-5° C. (ice/water bath). 41 ml of MeMgI in diethyl etherwere added dropwise to the solution so that temperature did not exceed5° C. (over 20 minutes). Reaction mixture was stirred and cooled to 0-5°C. Reaction was monitored by HPLC. Reaction was stopped after 4.5 h and200 ml of water were slowly added with external cooling. Reactionmixture was subsequently acidified with 12 ml of glacial acetic acid.Layers were separated and water layer was extracted with 100 ml oftoluene. Organic extracts were combined and dried over magnesiumsulfate. Mixture was filtered and solvent was evaporated to dryness(bath heated to 45° C.) giving 25.52 g of crude compound (11).

¹H NMR (Solvent: CDCl₃, Field [MHz]: 400)

Proton shift (ppm) Multiplicity J-coupling [Hz] Number of protons2.28-2.41 m 1 2.45-2.57 m 1 2.91-3.01 m 1 3.27-3.39 m 1 4.08 dd 8.0;12.0 1 7.17-7.73 m 13  8.00-8.10 m 2

EXAMPLE 2 Compound (11)

Work under argon.

24.50 g of compound (20) were dissolved in 180 ml of anhydrous toluene(distilled from benzophenone/Na). Solution was cooled to 0-5° C. (dryice/water bath). 41 ml of 3M MeMgCl in THF were added dropwise to thesolution so that temperature did not exceed 5° C. (over 30 minutes).Reaction mixture was stirred and cooled to 0-5° C. No precipitationobserved. Reaction was monitored by HPLC. Reaction mixture is turningcloudy—slight precipitation. Reaction was stopped after 3 h and 100 mlof water were slowly added with external cooling. Reaction mixture wassubsequently acidified with 3 ml of glacial acetic acid to pH=4-5.Layers were separated and organic extract was dried over anhydrousmagnesium sulfate. Mixture was filtered and solvent was evaporated todryness (bath heated to 45° C.) giving 20.05 g) of crude thiolactone(11) base.

HPLC—after evaporation—80.69%

EXAMPLE 3 Compound (11a)

2.586 g of thiolactone (11) were dissolved in 18 ml of toluene at 40° C.Solution was cooled to room temperature and 7.1 ml of 1M aqueous HClwere added with stirring. Mixture was stirred for 2 h at roomtemperature. Precipitated solid material was separated by suction andwashed with 5 ml of toluene and dried at room temperature.

HPLC: 95.43%

Yield: 1.43 g (63%)

EXAMPLE 4 Compound (11a)

2.182 g of thiolactone (11) was dissolved in 15 ml of toluene at 40° C.Solution was cooled to room temperature and 10 ml of 1M aqueous HCl wereadded with stirring. Thick precipitation has appeared so mixture wasdiluted with 5 ml of toluene. Mixture was stirred for 2 h at roomtemperature. Precipitated solid material was separated by suction andwashed with 5 ml of toluene and dried at room temperature.

HPLC: 87.56%

Yield: 1.48 g (77.26%)

EXAMPLE 5 Compound (11)

9.6 ml of 5% aqueous solution of NaHCO₃ were placed to 25 ml flask and10 ml of toluene were added. Mixture was stirred and 1.43 g of compound(11a) was added in portions. Suspension was heated to 40° C. (oil bathheated to 42° C.) for 1.5 h (all solid material was completelydissolved). Layers were separated and water layer was extracted with 5ml of toluene. Toluene extracts were combined and dried over anhydroussodium sulfate. Mixture was filtered and solvent was evaporated todryness (bath heated to 45° C.) giving foamy brownish solid material.

Yield: 0.132 g (89.90%)

HPLC: 91.93%

EXAMPLE 6 Compound (4)

Work under argon atmosphere

0.450 g of powdered anhydrous cerium (III) chloride were mixed with 1.44ml of anhydrous THF and mixture was stirred at room temperature for 16hours. Mixture was subsequently cooled to 0° C. and 0.96 ml of MeMgCl(3M THF solution) was added dropwise (over 5 minutes). Mixture wasstirred for 2.5 h at 0° C. In the mean time 0.234 g of thiolactone (11)was mixed with 7 ml of anhydrous toluene and mixture was heated to 60°C. until all solid material was dissolved. Solution was cooled to roomtemperature and subsequently added dropwise (over 5 min) to the mixtureof organometallic reagent at 0° C. Reaction mixture was stirred andcooled to 0° C. Reaction progress was monitored by HPLC:

after 50 min: R_(T)=13.12 min—94.54%

Reaction was stopped after 1 h and it was quenched with 2.5 ml of 1Maqueous HCl to pH=4-5 with external cooling. Color turned from orange tolight yellow. Mixture was stirred for 15 minutes at room temperature andlayers were allowed to separate. Water layer was extracted with 2×10 mlof ethyl acetate. Organic extracts were combined and washed with 10 mlof brine and with 10 ml of saturated sodium hydrogen carbonate solution.Organic layer was subsequently dried with sodium sulfate. Mixture wasfiltered and solvents were evaporated on the rotary evaporator (bathheated to 45° C.) giving partially crystalline yellow residue.

Yield: 0.23 g (93%) of crude material

EXAMPLE 7 Compound (11a)

Step 1

The compound (20) (254.3 g) was dissolved in anhydrous toluene (1870ml). Solution was cooled to 0-5° C. 3M solution of MeMgCl intetrahydrofuran (420 ml) was added dropwise via dropping funnel to thesolution of the compound (20) so that temperature did not exceed 5° C.(over 40 minutes). Reaction mixture was stirred and cooled to 0-5° C.Reaction was monitored by HPLC.

Reaction was stopped after 3 h and glacial acetic acid (72 ml) wasslowly added to the reaction mixture with external cooling (foaming).Cooling was interrupted and the reaction mixture was stirred for 10 min.It was subsequently diluted with water (500 ml) and resulting mixturewas stirred for 15 minutes at room temperature. Layers were separatedand organic extract was stored in the dark flask. It was used in thefollowing step without further purification or isolation.

Step 2

Concentrated HCl (54 ml) was slowly added to the solution of thiolactonebase prepared in the Step 1. Mixture was stirred for 1.5 h at roomtemperature and then stirred at 0-5° C. for another 1 h. Precipitatedsolid material was separated by suction and filter cake was washed withtoluene (2×150 ml). Solid thiolactone hydrochloride was dried at roomtemperature.

EXAMPLE 8 Compound (4)

Work under argon and in a dried glass equipment.

2.15 g of powdered anhydrous cerium trichloride was suspended in 6.90 mlof dry tetrahydrofuran and the mixture was stirred at laboratorytemperature for 19 hours. The white suspension was cooled down to 0° C.and 2.91 ml of 3M solution of methylmagnesium chloride (4.5 eq.) intetrahydrofuran was added dropwise. The mixture was stirred at 0° C. for1.5 hours and 1.00 g of the compound (20) (purity 87%, 1.938 mmol) in14.60 ml of dry toluene was added dropwise in the course of 20 minutes.The mixture was stirred at 0° C. for 265 minutes and then left inrefrigerator (8° C.) overnight (19 hours). As the reaction was foundincomplete by HPLC, 1.94 mg of 3M solution of methylmagnesium chloride(3 eq.) in tetrahydrofuran was added dropwise. The mixture was stirredat 8° C. for next 2.5 hours.

To the reaction mixture, 15 ml of water was added at 8° C. and themixture was stirred for 15 minutes. The pH value was adjusted by glacialacetic acid to 4-5 (approx. 4 ml), the mixture was filtered, the layersof the filtrate were separated and the aqueous layer was extracted with10 ml of toluene. Combined organic layers were dried over anhydroussodium sulfate and filtered.

Finally the toluene solution was concentrated.

Yield: 1.10 g

EXAMPLE 9 Compound (4b)

The toluene solution of the compound (4) was prepared according to theexample 8, starting with 8.5 mmol of the compound (20).

To the solution (approx. 100 ml), p-toluene sulfonic acid monohydrate(1.5 g) was added in several portions at room temperature and understirring. The mixture was stirred at room temperature for 1 hour. 25 mlof ethyl acetate was added and the mixture was stirred for next 20minutes.

The solid was collected by filtration and washed with 10 ml of ethylacetate.

Yield: 2.75 g, 96% purity.

EXAMPLE 10 Montelukast (Compound (1))

1.00 g of the tosylate (4b) was suspended in the mixture of 5.00 ml ofanhydrous tetrahydrofuran and 13.00 ml of methanol. Then, 0.42 g of thecompound (5a) was added. To the stirred mixture, a solution of 0.251 gof sodium methoxide in 3.0 ml of methanol was added dropwise in thecourse of 40 minutes at 20° C. The mixture was stirred at laboratorytemperature for 21.5 hours. Then, 0.31 g of sodium hydroxide in 1.5 mlof water was added at once and the mixture was heated at 55° C. for 105minutes. Then 10 ml of toluene was added and volatile solvents(methanol, tetrahydrofuran) were removed on a rotary vacuum evaporator(50° C.). 6 ml of water was added and the pH value was adjusted with 0.5ml of glacial acetic acid to 5. The mixture was stirred for 15 minutesand then allowed to stand for separation of layers. The aqueous layerwas extracted with 2×10 ml of toluene under argon.

Combined organic layers were concentrated, 5 ml of dichloromethane wasadded and concentrated again. The residue was mixed with 10 ml oftoluene, heated to 35° C., seeded with a crystal of montelukast and keptat this temperature for 20 hours. The mixture was filtered after coolingto 20° C., the solid washed with 2×2 ml of toluene. Solid crystallineproduct was dried at 20° C. protected from light.

Yield: 0.47 g. Purity (HPLC) 96.93%. Content of the ketone compound (14)0.03%.

EXAMPLE 11 Compound (4)

98 g of anhydrous cerium (III) chloride was mixed with 370 ml ofanhydrous tetrahydrofurane and the mixture was stirred at 20-25° C. for13 hours. The mixture was then cooled to 0-5° C. and 132 ml of 3Msolution of methylmagnesium chloride in tetrahydrofurane was addeddropwise in 5 minutes. The mixture was stirred for 2.5 hours at 0-5° C.

Separately, 50.5 g of compound (11) was placed into a 2 l flask anddissolved in 550 ml of anhydrous tetrahydrofuran under stirring at20-25° C. The solution was then cooled to −10 to −15° C. and theprepared pre-cooled mixture of cerium chloride/methylmagnesium chloridewas added to the solution of compound (4) over 3 minutes at −10 to −15°C. The mixture was stirred at the same temperature under HPLC controland the reaction was stopped after 50 minutes. A solution of 36 ml ofglacial acetic acid in 250 ml of water was slowly added to the reactionmixture at −5 to 0° C. in 2 minutes and the mixture was stirred for 15minutes at room temperature. Layers were separated and the aqueous layerwas washed with 100 ml of tetrahydrofuran. Combined organic extractswere washed with 3×100 ml of saturated aqueous NaHCO₃ and with 200 ml ofbrine, dried by magnesium sulfate and filtered giving 950 ml of thesolution of compound (4) in tetrahydrofurane. Purity: 96.00% (HPLC, IN)

EXAMPLE 12 Solid State Acid Addition Salts of (20)

a) Compound (20a)

152 g of compound (20) was mixed with 457 g of ethyl acetate and themixture was heated to 65-70° C. Gaseous HCl (at least one molarequivalent) was bubbled through the stirred solution (NB. alternately,saturated solution of HCl in ethyl acetate, ethanol or isopropanol maybe used as well). The resulting suspension was cooled to 0-5° C. andstirred for 2 hours. The formed crystals were separated by filtrationand washed by cold ethyl acetate. Crystals were dried at 60° C. underreduced pressure for 12 hours.

Yield: 153 g of yellow crystals, m.p. 168° C.

b) Compound (20b)

15.6 g of compound (20) and 24 g of acetone were heated under stirringto 30-40° C. 5.3 g of benzenesulfonic acid was added to the solution.After approx. 3 minutes, crystals started to separate. The suspensionwas cooled to 25° C. and stirred for 30 minutes. The solid product wereseparated by filtration and washed with cooled acetone. Crystals weredried at 60° C. under reduced pressure for 12 hours.

Yield: 9 g of yellow crystals, m.p. 96-97° C.

c) Compound (20c)

17.9 g of compound (20) was suspended in a mixture of 16 g acetone and47g isopropanol and the mixture was heated under stirring to 60° C. 7.3g of p-toluenesulfonic acid monohydrate was added, the resulting mixturewas cooled to 25° C. and stirred for 8 hours. Crystals were separated byfiltration and washed with 20 g of cooled isopropanol. Crystals weredried at 60° C. under reduced pressure for 12 hours.

Yield: 12.4 g of yellow crystals, m.p. 78.5° C.

d) Compound (20d)

17.2 g of compound (20) was mixed with 120 g of acetone and, understirring, 3.7 g of 98% sulfuric acid was added slowly. The mixture wascooled to 25° C. The solid product was separated by filtration andwashed with 20 g of cooled acetone. Crystals were dried at 60° C. underreduced pressure for 12 hours.

Yield: 4.1 g of yellow crystals, m.p. 90° C.

EXAMPLE 13 Compound (5b) [R=methyl]

Work under argon.

14.71 g of compound (15) [R=methyl] was dissolved in 41 ml of anhydrouspyridine. The mixture was cooled to 0° C. and 25.05 g ofp-methoxybenzenesulfonyl chloride was added portionwise within 7 minutesso that the temperature did not exceed 7° C. The mixture was stirred for6 hours at 0° C. Conversion was monitored by TLC (silica gel 60 F254Merck, 10% acetone in toluene (v/v), UV 254 nm). The mixture was dilutedwith 100 ml of dichloromethane at −10° C., 34.2 ml of concentrated HClwas slowly added in such a way that the temperature did not exceed 0° C.and the formed two layers were allowed to separate. The aqueous layer(pH<1) was extracted with 50 ml of dichloromethane and combined organiclayers were washed with 50 ml of water, 50 ml of saturated aqueousNaHCO₃ and 50 ml of brine. The organic layer was dried by MgSO₄ andvolatiles were evaporated at 35° C. and 20 torr.

Yield: 34.12 g of pale yellow oil.

EXAMPLE 14 Montelukast (1)

1.89 g of the compound (5b) was dissolved in 15 ml of toluene and thesolution was cooled to 5° C. Then, 3.5 ml of 24% methanolic solution ofsodium methoxide was added. At the same temperature, a solution of 2.37g of compound (4) in 44 ml of tetrahydrofuran was added dropwise during6 minutes. The mixture was stirred at 10° C. for 23 hours under HPLCcontrol.

Mixture was cooled to 0° C. Then a solution of 1.44 ml of acetic acid in25 ml of 5% aqueous NaCl was added in such a way that the temperaturedid not exceed 2° C. Clear aqueous layer was separated and the organiclayer was washed with 4×20 ml of an aqueous solution containing 2%NaHCO3 and 5% NaCl and then with 20 ml of brine. The organic layer wasthen dried over MgSO4, filtered and the volatiles evaporated at 45° C.at reduced pressure. The obtained yellow oil was dissolved in 3 ml ofhot toluene and the mixture was stirred at room temperature overnight.Solid precipitate was filtered off and dried yielding 2.48 g of a paleyellow solid.

EXAMPLE 15 Purification of Montelukast

19.7 g of montelukast (purity 93.2%) was dissolved in 180 ml of tolueneat 96° C. and the solution was cooled to 65° C. 2.0 g of silica gel(Merck, SiO₂ 60, 40-63 microns, 230-400 mesh) was added and the mixturewas stirred for 10 minutes. Silica gel was filtered off and washed with20 ml of hot toluene (65° C.). The filtrate was gradually cooled down to28° C., precipitated solid product was filtered and washed with 2×5 mlof cold toluene. Yield: 16.39 g of pre-purified montelukast, purity(HPLC, IN) 97.54% optical purity (HPLC, chiral column) 99.5%.

16.10 g of the pre-purified montelukast was dissolved in 160 ml oftoluene at 100° C. and the mixture was gradually cooled down to 25° C.The solid product was filtered off and washed with 2×5 ml of coldtoluene.

Yield: 15.43 g of purified montelukast, purity (HPLC, IN) 98.24%.

15.20 g of the purified montelukast was dissolved in 77 ml of absoluteethanol under absence of light at 80° C. (bath temperature) and themixture was cooled to 25° C. The solid product was filtered off andwashed with 2×5 ml of cold ethanol.

Yield: 12.97 g of pure montelukast, purity (HPLC, IN) 99.0%, opticalpurity 99.65%

EXAMPLE 16 Montelukast Sodium Amorphous

2.0 g of Montelukast was dissolved in 5 ml of a toluene-methanol mixture(4:1 v/v) at 50° C. The turbid solution was cooled under stirring to 25°C. At this temperature, 0.33 ml of aqueous NaOH solution (0.15 g, 3.75mmol) was added dropwise within 20 minutes. The solution was maintainedat this temperature for 30 minutes, 0.05 g of activated charcoal wasadded and the suspension was filtered through Celite filter. The Celitewas washed with 2×2 ml of toluene. The combined solution was evaporatedalmost to dryness under reduced pressure at bath temperature 38° C.Yellow viscous oil was obtained.

The oil was added dropwise into 10 ml of stirred n-heptane and stirredfor 15 minutes at 25° C. White precipitate was formed. Then the mixturewas stirred at 25° C. for next 17 hours. The precipitate was filtered bysuction, washed with 2×10 ml of n-heptane and dried at room temperatureprotected from light.

Yield 1.85 g of white amorphous solid.

EXAMPLE 17 Preparation and Purification of Compound (11)

3.10 kg of the compound (20a) (purity 95%) were dissolved in 31 L ofanhydrous toluene. Solution was cooled to 0° C. and 5.84 L of 3M MeMgClin THF were added dropwise to the solution so that temperature did notexceed 5° C. during 60 to 75 minutes. Temperature was raised to 15° C.and Reaction mixture was stirred at 15° C. for 3 hours. Then 18 L ofwater were slowly added. Aqueous layer was discharged and reactionmixture was subsequently acidified with 1.50 kg of glacial acetic acidin 13.0 kg of water to pH=4-5. Layers were separated and the organicextract was extracted with saturated aqueous sodium bicarbonate and thenpartially concentrated to about one half at reduced pressure (35° C.).Concentrated solution was warmed to 85° C., 3.0 kg of ethyl acetate and2.0 kg of ethanol was added and the refluxed mixture was cooled down to0° C. Solid product was filtered off giving 1.6 kg of crude thiolactone(11) base (HPLC purity >95%).

The thiolactone base was dissolved in 7.5 kg of tetrahydrofurane at 60°C., methanol (7.5 kg) was added under stirring in 30 minutes and thesolution was slowly cooled to 0 C. The precipitated solid was filteredand washed with 500 g of methanol. Yield 1.56 kg of the compound (11)with a HPLC purity >99%.

Each of the patents, patent applications, and journal articles mentionedabove are incorporated herein by reference The invention having beenthus described, it will be obvious to the worker skilled in the art thatthe same may be varied in many ways without departing from the spirit ofthe invention and all such modifications are included within the scopeof the present invention as set forth in the following claims.

1. A process for the purification of montelukast acid, which comprisesfiltering a toluene solution of montelukast acid through a polarsorbent.
 2. The process according to claim 1, wherein said polar sorbentis silica gel.
 3. The process according to claim 1, which furthercomprises precipitating the montelukast acid from said toluene solutionafter said filtering step.
 4. The process according to claim 3, whichfurther comprises, crystallizing said montelukast acid precipitate froma protic solvent in the absence of light.
 5. The process according toclaim 4, wherein said protic solvent is an alcoholic solvent.
 6. Theprocess according to claim 5, wherein said alcoholic solvent is ethanol.7. The process according to claim 4, wherein said filtering is performedat least twice before said crystallizing step.
 8. The process accordingto claim 4, wherein said crystallized montelukast acid has a purity ofgreater than 99%.
 9. The process according to claim 8, wherein saidcrystallized montelukast acid has a purity of greater than 99.5%.
 10. Aprocess for the purification of montelukast acid, which comprisescrystallizing montelukast acid from a protic solvent in the absence oflight.
 11. The process according to claim 10, wherein said proticsolvent is an alcoholic solvent.
 12. The process according to claim 11,wherein said alcoholic solvent is ethanol.
 13. The process according toclaim 10, wherein said crystallized montelukast acid has a purity ofgreater than 99%.